Confounding, ascertainment bias, and the blind quest for a genetic ‘fountain of youth’

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Many promises have been made about the impact of the Many promises have been made about the impact of the Human Genome Project on clinical practice and public Human Genome Project on clinical practice and public health, yet despite massively funded efforts over the past health, yet despite massively funded efforts over the past decade, little headway has been made in elucidating the decade, little headway has been made in elucidating the specic genetic factors which have major impact on the risk specic genetic factors which have major impact on the risk of developing common complex traits.There are two of developing common complex traits.There are two fundamental reasons for this abject failure as follows: 1) fundamental reasons for this abject failure as follows: 1) studies have been inadequately designed to identify such studies have been inadequately designed to identify such genetic risk factors; 2) the genetic factors that do exist are genetic risk factors; 2) the genetic factors that do exist are individually of small marginal importance, and are charac-individually of small marginal importance, and are characterized by extensive heterogeneity.If 2) is the truth, there is terized by extensive heterogeneity.If 2) is the truth, there is little we can do about it, so we emphasize the importance of little we can do about it, so we emphasize the importance of 1) in this article, while recognizing that 2) probably is not 1) in this article, while recognizing that 2) probably is not far from the truth.Genetic studies, in contrast to far from the truth.Genetic studies, in contrast to epidemiological studies, use confounding and ascertain-epidemiological studies, use confounding and ascertainment bias to help identify weak etiologic signal due to ment bias to help identify weak etiologic signal due to genes, since gene mapping is fundamentally a hypothesis-genes, since gene mapping is fundamentally a hypothesisfree science.This strategy makes it possible to identify free science.This strategy makes it possible to identify genetic risk factors, but makes it impossible to quantify the genetic risk factors, but makes it impossible to quantify the size of their effect on risk.Classical epidemiological study size of their effect on risk.Classical epidemiological study designs are of minimal value for gene identication, but designs are of minimal value for gene identication, but may be of use in estimation of the effect size of genetic risk may be of use in estimation of the effect size of genetic risk factors once they are identied in more appropriately factors once they are identied in more appropriately designed genetic studies.However, if the effects are so designed genetic studies.However, if the effects are so weak that we need this strong, systematic ascertainment weak that we need this strong, systematic ascertainment bias to nd them, their relevance to public health may be of bias to nd them, their relevance to public health may be of questionable immediate value, raising many questions about questionable immediate value, raising many questions about the rhetoric and promises being made to the public as the rhetoric and promises being made to the public as justication for justication for `big science big science' ' approaches to dissecting the approaches to dissecting the hypothetical role of genes in complex traits.hypothetical role of genes in complex traits.